Sie sind auf Seite 1von 7

ANTIMICROBIAL AGENTS AND CHEMOTHERAPY, Sept. 1991, p. 1765-1771 Vol. 35, No.

9
0066-4804/91/091765-07$02.00/0
Copyright ©) 1991, American Society for Microbiology

Effects of Ranitidine and Sucralfate on Ketoconazole Bioavailability


STEPHEN C. PISCITELLI,lt THOMAS F. GOSS,l.2* JOHN H. WILTON,2 DAVID T. D'ANDREA,2
HARVEY GOLDSTEIN,3 AND JEROME J. SCHENTAG' 2
Center for Clinical Pharmacy Research, School of Pharmacy, State University of New York
at Buffalo, Amherst, New York 14260,' and The Clinical Pharmacokinetics Laboratory 2*
and Department of Medicine,3 Millard Fillmore Hospital, Buffalo, New York 14209
Received 24 September 1990/Accepted 5 July 1991

Ketoconazole is an oral imidazole antifungal agent useful in the treatment of opportunistic fungal infections.
Gastrointestinal absorption of this agent is variable and dependent on the presence of gastric acid. This study
compared the effects of concomitant sucralfate administration with ranitidine administration on the pharma-
cokinetic disposition of a 400-mg ketoconazole dose. Six healthy male volunteers were randomized to receive
400 mg of ketoconazole alone, 1.0 g of sucralfate concomitantly with a 400-mg ketoconazole dose, or ranitidine,
administered 2 h prior to a 400-mg ketoconazole dose to titrate to a gastric pH of 6. All subjects received all
three regimens in crossover fashion. Gastric pH was measured continuously for 4 h after ketoconazole
administration in all subjects by using a Heidelberg radiotelemetry pH capsule. Relative ketoconazole
bioavailability was compared between treatments. With sucralfate, five of six subjects demonstrated a decrease
in the peak drug concentration in serum as well as an increase in the time to peak concentration, indicating a
delay in ketoconazole absorption. The mean area under the concentration-time curve from 0 to 12 h for
ketoconazole following gastric alkalinization was significantly different from that of either ketoconazole alone
or ketoconazole with sucralfate (P < 0.01). Continuous gastric pH monitoring allowed correlation between the
decrease in ketoconazole bioavailability observed with ranitidine and the increase in gastric pH. The apparent
decrease in ketoconazole bioavailability observed with sucralfate appears to be caused by an alternative
mechanism since a change in gastric pH was not observed. On the basis of these findings, separating the
administration of ketoconazole and sucralfate should be considered to decrease the potential for interaction of
sucralfate on ketoconazole bioavailability.

Ketoconazole is an oral antifungal agent of the imidazole Sucralfate may also reduce the likelihood of alimentary tract
class. It is used for the treatment of systemic opportunistic colonization with potential pathogens (20). Presumably,
fungal infections which commonly occur in oncology pa- many of the same patients requiring ketoconazole may also
tients undergoing radiation or chemotherapy and in other benefit from concomitant sucralfate therapy when these
immunocompromised hosts (1, 6, 10, 12). Although a clinical complications arise.
correlation has not been demonstrated, it is assumed that Sucralfate is a complex of sulfated sucrose and aluminum
successful treatment requires ketoconazole concentrations hydroxide. Administration of this agent has been shown to
exceeding the MIC for the organism. Antifungal efficacy, lower concentrations of norfloxacin and phenytoin, but
like antibacterial efficacy, is theoretically dependent on the neither prednisone nor erythromycin, in plasma (8, 11, 16,
area under the concentration-time curve (AUC) of the anti- 18). Since sucralfate has not been reported to alter gastric
fungal agent above MIC and on the duration of time the acidity, these interactions are thought to result from binding
serum antifungal concentrations remain above the MIC at of the affected drug to either the aluminum or sulfated
the site of infection. Comparing the AUCs achieved under sucrose moiety and not from changes in gastric pH (15, 17).
differing dosing conditions is appropriate to assess changes In this study, gastric pH was monitored to aid in assessing
in relative bioavailability and, in turn, presumed antifungal the mechanistic role of pH on any observed effects of
efficacy. sucralfate and the H2 antagonist ranitidine on ketoconazole
Studies assessing the bioavailability of ketoconazole have pharmacokinetics.
documented that absorption is variable and pH dependent,
with highest concentrations in serum achieved at low gastric MATERIALS AND METHODS
pH (25). Therefore, to ensure maximum effectiveness, keto-
conazole should not be administered concomitantly with Six healthy male volunteers between the ages of 18 and 30
agents that increase gastric pH such as antacids and H2 participated in this study. The study was approved by the
antagonists (14). Millard Fillmore Hospital Human Research Committee, and
Treatment of the cancer patient may lead to mucositis and written informed consent was obtained from all subjects.
esophagitis due to desquamation of the alimentary tract (13). Health status was assessed by medical history, laboratory
In addition to proof of safety and efficacy in the treatment of profiles, and physical exam. Subjects were required to be
peptic ulcer disease, sucralfate has been reported to improve nonsmokers and were not permitted to take any other
healing and relieve pain associated with mucositis (7, 21). medications for 48 h before and during all study treatments.
Subjects were randomized to a treatment sequence which
was administered in a three-way crossover, Latin square
*
Corresponding author. design to control for order of treatment effects. Each study
t Present address: University of Illinois at Chicago, Chicago, IL treatment was separated by 1 week. Treatment I consisted of
60637. a single oral 400-mg dose of ketoconazole (lot 98H130;
1765
1766 PISCITELLI ET AL. ANTIMICROB. AGENTS CHEMOTHER.

TABLE 1. Serum ketoconazole concentration data


Relative
Treatmenta Subject nlo.
TreatmetaSubjct no.AUCO-12
(mg hMiter) C..x
(g/m) (h.-1)
max (h
K (h-) bioavailability
(AUCO12)
Median
4-h pH
(mg h/liter)
I 001 28.35 6.35 2.00 0.407 1.00 2.36
002 48.99 9.04 2.50 0.461 1.00 1.84
003 38.76 11.78 1.00 0.244 1.00 4.21
004 47.42 8.42 3.00 0.405 1.00 3.25
005 27.35 7.59 0.50 0.312 1.00 1.63
006 31.41 6.03 1.50 0.512 1.00 4.38
Mean 37.05 8.20 1.75 0.390 1.00 2.95
SD 9.54 2.10 0.94 0.089 0.00 1.19
II 001 31.85 6.62 2.50 0.645 0.123 2.09
002 38.91 6.25 4.00 0.445 0.794 1.89
003 26.39 5.59 3.00 0.358 0.681 1.59
004 36.33 6.17 3.00 0.364 0.766 3.24
005 21.03 5.28 2.00 0.390 0.769 1.73
006 20.53 2.41 6.00 0.177 0.654 1.27
Mean 29.17 5.39 3.42 0.3% 0.798 1.97
SD 7.77 1.54 1.43 0.138 0.170 0.68
III 001 1.23 0.43 4.00 NDb 0.043 6.20
002 0.29 0.25 1.50 ND 0.006 7.35
003 2.49 0.% 4.00 ND 0.064 7.31
004 0.32 0.28 2.00 ND 0.007 6.36
005 5.44 1.51 2.50 ND 0.199 5.79
006 0.06 0.24 1.50 ND 0.002 6.79
Mean 1.64 0.61 2.58 ND 0.050 6.72
SD 2.07 0.52 1.16 ND 0.080 0.66
a
Treatment I, ketoconazole (400 mg); treatment II, ketoconazole (400 mg) plus sucralfate (1 g); treatment III, ketoconazole (400 mg) plus ranitidine (150 mg).
b ND, not done.

Janssen Pharmaceutica). For treatment II, subjects received administered in suspension to simulate the regimen reported
1.0 g of oral sucralfate (lot H9507; Marion Laboratories) four to provide symptomatic relief of stomatitis in cancer patients
times daily for 2 days prior to ketoconazole administration, (7, 21). During treatment III, subjects received 150 mg of
and then an extemporaneously compounded sucralfate sus- ranitidine (lot Z10989FP; Glaxo) orally every 12 h for 2 days
pension (1.0 g in 30 ml of water) was administered 5 min prior to ketoconazole administration, and then 150 mg was
before the 400-mg oral ketoconazole dose. Sucralfate was administered orally 2 h before the 400-mg oral ketoconazole

iK
E
a
4
U
z
a
0
3
I.-
h
x
2

HOURS
a KrTO KETO/SUCR
+ 0 KETO/RAN
FIG. 1. Mean ketoconazole serum concentration for each study phase.
VOL. 35, 1991 KETOCONAZOLE BIOAVAILABILITY 1767

a 9 -9. 0

8. c - 8. 0

7. -7. 0

6. \- - - -6. 0
5. ( 5. 0
pH - Drug conc.
4. -4.0

3. -3. 0

2. i -2. 0

1.I 1. 0

0. -0. 0
1 2 3 4 5 6 7 8 9 10 11
Time in Hours

9. *9. 0

8. 8. 0
7. 7. 0

6.I *6. 0

5. 5. 0
pH Drug conc.
4. *4. 0

3. -3. 0

2. -2. 0

1. 1. 0

0. 0o. 0

Time in Hours

9. 0
C 9. 0-
8. 0- 6. 0

7. 0- 7. 0

6. 0- 6. 0

5. 0- 5. 0
pH Drug conc.
4. 0- *4. 0
3. 0 3. 0

2. 0 .2. 0

1. 0o 1.0

0. 0 0. 0
0 1 2 3 4 5 6 7 9 10 11 1 2
Time in Hours
*****Geoanetric mean of pH at 15 min intervol
eweaa Drug concentration in the blood

FIG. 2. Serum ketoconazole concentration versus time for ketoconazole alone (treatment I) (a), ketoconazole with sucralfate (treatment II)
(b), and ketoconazole with ranitidine (treatment III) (c) for subject 002. Four-hour gastric pH recording is also illustrated.
1768 PISCITELLI ET AL. ANTIMICROB. AGENTS CHEMOTHER.

dose. During treatment III, a 50-mg intravenous dose of (percent coefficient of variation) of the study standard curves
ranitidine (lot B6049Ca; Glaxo) was allowed if gastric pH fell was 2.54%. The overall precisions of the seeded quality
below 6.0 at any time in the 4-h period after ketoconazole controls at concentrations 30.0, 10.0, 3.00, and 0.60 jig/ml
administration. A maximum of two doses of intravenous were 4.25, 2.49, 0.80, and 3.46%, respectively.
ranitidine was permitted. Additional doses were necessary Pharmacokinetic analysis. Serum concentration-versus-
for subjects 2 and 3, who required one 50-mg ranitidine time data were fit by using PCNONLIN (22). Data were fit to
injection, and subjects 1, 4, and 5, who required two 50-mg a one-compartment model with first-order absorption and
injections, to maintain a gastric pH greater than 6 during the first-order elimination to estimate the elimination rate con-
monitoring period. stant (kel). The AUC was estimated by using the linear
Subjects fasted for 8 h before each study day and ab- trapezoidal rule from 0 to 12 h, and for treatments I and II,
stained from alcohol for at least 48 h before taking study addition of the area approximated by the last measurable
medications. Compliance was assessed by subject interview concentration-time point/Kel was used to extrapolate the
on each study day. AUC to infinity (9). As there were few measurable concen-
The subjects' gastric pH was monitored continuously for 4 trations in serum during the ranitidine treatment of the
h after ketoconazole administration in each study treatment study, estimation of the terminal Kel was not possible;
by using an ingestible Heidelberg pH transmitting radiote- hence, it was not possible to assess total body clearance and
lemetry capsule. The Heidelberg capsule was suspended in noncompartmental parameters which are dependent on an
the stomach by using sterile suture material. The free end of accurate estimation of K,1.
the string was secured to the outside of the subject's cheek Statistical analysis. Single-factor analysis of variance for
to prevent passage of the capsule from the stomach. Correct repeated measures was used to test whether significant
positioning of the Heidelberg capsule was verified by the differences in ketoconazole bioavailability (AUC) existed
observed pH data and a radio-locating (signal peaking) between treatments. Tukey's multiple comparison test was
technique. The pH was monitored continuously by a belt performed when a difference was noted. An alpha value of
antenna worn by each subject. The antenna was connected 0.05 was determined a priori.
to a Clinical Pharmacokinetics Laboratory-designed TE-
2000 receiver to convert the capsule signal to a pH value and RESULTS
measure received signal strength and quality. The receivers
were connected to an IBM-PC XT computer with software All six subjects completed the study. Adverse effects
designed to calculate a 5-min geometric mean pH by using 60 which occurred during the study were minor. Two subjects
samplings per subject taken during that period. The program had complaints of mild nausea, and one subject reported a
also allowed the operator to enter comments regarding headache; all resolved without treatment. Evaluation of
adverse effects, time of dose, and ingestion of water, etc. A post-study laboratory tests revealed that one subject had an
description of the Heidelberg capsule and the Clinical Phar- elevated serum creatinine concentration which was not
macokinetics Laboratory TE-2000 receiving system has thought to be medication related and was noted to be normal
been published (4, 23, 24, 26). on follow-up.
Blood samples were obtained from an indwelling venous Mean serum ketoconazole concentration data collected
catheter at 5 min prior to ketoconazole dosing and 0.5, 1.0, for each subject during each treatment of the study are
1.5, 2.0, 2.5, 3.0, 4.0, 6.0, and 12 h postdosing. Twenty-four- summarized in Table 1 and include the AUC from 0 to 12 h
hour samples were obtained by direct venipuncture. Ap- (AUCO-12), peak drug concentration in serum (Cmax), time to
proximately 5 ml of blood was collected per sample in peak concentration (Tmax), Kei (treatments I and II), and
Vacutainer tubes (Becton Dickinson Vacutainer Systems, relative bioavailability for each treatment compared with the
Rutherford, N.J.), allowed to clot, and then centrifuged. AUC achieved during the control treatment. A decrease in
Serum was separated and immediately frozen at -20°C until Cmax was observed in five subjects during the sucralfate
analyzed. treatment compared with the control treatment, while a
Ketoconazole assay. Ketoconazole concentrations in se- nominal increase was observed in one subject. An increase
rum were assayed at The Clinical Pharmacokinetics Labo- in Tmax was observed in five subjects whereas one subject
ratory by using reverse-phase high-performance liquid chro- exhibited no change during the concomitant treatment with
matography using a modification of the method described by sucralfate. During the ranitidine treatment, a large decrease
Riley and James (19). Equipment consisted of a high-perfor- in Cmax was observed in all subjects while only three of six
mance liquid chromatography pump (model 6000A; Waters, subjects showed an increase in Tmax.
Inc.), an autosampler (model SP8780; Spectra-Physics), an The mean AUCs for the three treatments are shown in Fig.
integrator (model SP4270; Spectra-Physics), and a UV de- 1. Only subject 1 had a higher ketoconazole AUC -12 after
tector (model 757; Kratos Spectroflow) set at 254 nm. The concomitant administration of sucralfate than at baseline
analytical column used was a Waters Novopak C18 (3.9 mm (Table 1). All subjects had a lower AUCO_12 during the
by 15 cm). The mobile phase, which consisted of 300 ml of ranitidine treatment than during the other two treatments.
methanol, 300 ml of acetonitrile, and 350 ml of 0.02 M For the ranitidine treatment, all of the 12- and 24-h samples
monobasic potassium phosphate, was adjusted to pH 6.8, as well as the majority of the other samples had concentra-
filtered, and degassed before use at a flow rate of 2.0 mllmin. tions below the minimum detectable concentration of the
Retention times of ketoconazole and clotrimazole, the inter- assay. This observation leads us to conclude the difference
nal standard, were 4.3 and 7.0 min, respectively. Serum in ketoconazole bioavailability was not due to delayed
samples were thawed at room temperature, and a 1.0-ml absorption; rather, it was likely due to decreased ketocona-
aliquot was prepared over a C18 solid-phase extraction zole dissolution. Relative to the control, the average bio-
column (part 607303; Analytichem). availability for ketoconazole was 80% when administered
Serum standard curves were linear over a concentration with sucralfate and 5% with ranitidine.
range of 0.2 to 12 ,g/ml. Concentrations below 0.2 p,g/ml The differences in AUCO_12 observed between treatments
were reported as not detectable. The overall precision I and III and between treatments II and III were statistically
VOL. 35, 1991 KETOCONAZOLE BIOAVAILABILITY 1769

50T

40+
C) ------------
------------ I

4 I
I
" 0
30-
0 I
I
- SMJLATION K
44 * RANTIDINE
° 20. ,4. 1.I
I
* CONTROL

09
Ei
U-.
I
I

10+ I

,It

a
U4I

i I I T l-lI I
0 1 2 4 5 6 7 8

MEDIN 4 HR pH
FIG. 3. Simulated ketoconazole bioavailability at different gastric pHs (--- -) based on in vitro dissolution data compared with actual
patient data during control and ranitidine treatments.

significant (P < 0.01). However, a 20.2% mean decrease in tion is delayed and incomplete. Figure 3 represents ketocon-
AUCO, 12 noted between ketoconazole treatment alone and azole AUC (in milligrams hours per liter) versus median
its concomitant administration with sucralfate was not sta- 4-h pH for the ketoconazole (control) and ranitidine treat-
tistically significant, and failure to detect such a difference ments which provides a strong correlation between bioavail-
may be due to a combination of small sample size and large ability and pH-dependent dissolution. The line superim-
variability in ketoconazole absorption. A sample size calcu- posed on this plot represents a simulation of the AUC which
lation performed prior to study initiation indicated that a would be expected by administration of the same oral dose at
94% difference in bioavailability would be detectable with different gastric pHs, based on percent ketoconazole disso-
alpha = 0.05, beta = 0.1, power = 0.9, and a variance of 13% lution from the in vitro data. The initial AUC for the
of the mean. This difference was detected for treatment with
ranitidine. simulation represents the mean treatment I AUC,,12 (37.05
The mean 15-min pH versus concentration versus time mg h/liter). This simulation assumes that at pH 1 there is
graphs are shown in Fig. 2 for a representative subject 100% dissolution and 100% absorption and that absorption is
(subject 002). During treatment III (Fig. 2c), the low proportional to percent dissolution at every pH. The percent
AUCO12 for ketoconazole was associated with a consis- dissolution at each pH value was estimated by using the in
tently elevated gastric pH in all subjects during the 4-h vitro dissolution data provided by Carlson and coworkers
period following ketoconazole administration. This elevation and plotted at pH 2, pH 3, pH 4, pH 5, pH 6, and pH 7 (3).
is best represented by the median 4-h gastric pH data This figure represents the fraction dissolved multiplied by
provided in Table 1 (pH 7.35 for subject 002). With concom- the mean treatment I AUC. As indicated by the simulation
itant sucralfate administration, there appears to be a de- curve, there appears to be a sharp decrease in ketoconazole
crease in ketoconazole bioavailability although there was no dissolution between pH 4 and 5, resulting in a sharp decrease
difference in median 4-h pH compared with that for the in bioavailability. Our results fit this simulation well. Figure
control treatment (Fig. 2a and b, respectively), with median 4 also represents the relationship between the fraction of
4-h pHs of 1.89 in treatment II and 1.84 in treatment I for AUC for each treatment compared to baseline versus me-
subject 002. dian 4-h pHs. Again, a trend indicating decreased fraction
absorbed with increasing gastric pH is observed.
DISCUSSION The concomitant administration of ketoconazole with su-
cralfate resulted in a 20.2% mean decrease in ketoconazole
This study confirms that significant reduction in bioavail- bioavailability. In contrast to the result for ranitidine, eleva-
ability of ketoconazole is associated with an increase in tion of gastric pH does not explain this change. Sucralfate
gastric pH. When gastric pH was titrated above 6.0, the appeared to delay the absorption of ketoconazole as evi-
AUCO, for ketoconazole was reduced by 95%.
12 denced by a mean increase in the Tmax of 1.67 h. Results for
The most plausible explanation for the changes in keto- all subjects showed an increase in this parameter, except one
conazole absorption observed during the ranitidine treat- that demonstrated no change. This is consistent with the
ment of this study is decreased ketoconazole dissolution at effects of sucralfate administration reported for other medi-
pH >5. This is consistent with in vitro work reported by cations such as naproxen and prednisone (2, 8).
Carlson and coworkers which demonstrated that dissolution Previous authors have noted the lack of effect of sucralfate
of ketoconazole is rapid and complete (>90%) at pH <4 (3). on gastric pH (15, 17). This study supports these observa-
However, at pHs of 5 and 6, in vitro ketoconazole dissolu- tions but gives no definitive explanation for the apparent
1770 PISCITELLI ET AL. ANTIMICROB. AGENTS CHEMOTHER.

1.--
0

1- 0* *

L 0.6
z
41 a0 0
-J
w 0 0
< 0.6-1+
m
9 0.4.
I.-
C)I-,
lir
0.3-If
I 5 6 7 a
MEDIAN 4H pH
FIG. 4. Fraction of AUC achieved in treatments II and III compared with treatment I versus median 4-h (4H) gastric pH.

decrease in ketoconazole AUCO- 12 in five of six subjects conazole absorption observed with ranitidine and sucralfate
after concomitant sucralfate administration. administration. In addition, using the Heidelberg capsule
The Heidelberg capsule technology used in this study allowed for a decrease in the sample size required to conduct
proved to be valuable in assessing drug-drug interaction this study. Control of pH to a specified target range allowed
mechanisms with regard to the effect of pH. As no change in precise determination of the impact of alkaline pH in a
pH was noted between treatments I and II, binding of setting where baseline gastric pH was variable. This pH
ketoconazole to sucralfate in the gastrointestinal tract re- control, therefore, improved the assessment of the associa-
mains a strong possible explanation for the observed 20% tions between gastric pH 4nd ketoconazole bioavailability.
decrease in bioavailability but is not proven by this study. Many questions remain for further'study. An avenue for
A statistically significant decrease in ketoconazole bio- further study would be an in vitro evaluation of a possible
availability was not associated with sucralfate administration interaction between ketoconazole and sucralfate by the
even though bioavailability decreased 20.2%. Since the in formation of chelates. Clearly,'the concurrent administration
vitro MICs of ketoconazole for various fungal organisms of agents which increase gastric pH should 'be avoided in
exhibit an extremely wide range, are method dependent, and patients treated with ketoconazole therapy.
do not necessarily correlate well to 'in vivo efficacy, this
potentiai decrease in ketoconazole bioavailability (AUCO.12) ACKNOWLEDGMENTS
associated with concomitant sucralfate administration may We thank the CRC Staff at the Clinical Pharmacokinetics Labo-
be clinically significant (5). However, this potential decrease ratory for their assistance in conducting this study and Audrey L.
in relative ketoconazole bioavailability after concomitant Berowski for her assistance with manuscript preparation.
sucralfate administration was highly variable as measured by This study was sponsored in part, by a grant from Upjohn, Co.,
AUCo_2 and ranged from a 12.3% increase in subject 001 to Kalamazoo, Mich.
a 31,9% decrease in subject 003. Therefore, the data here do
not preclude the concomitant use of sucralfate and ketocon- REFERENCES
azole, although this wide variability suggests that in some 1. Bodey, G. P. 1966. Fungal infections complicating acute leuke-
patients, clin cal failure could be associated with concomi- mia. J. Chronic Dis. 19:666-689.
2. Caille, G., P. duSouich, P. Gervais, J. G. Besner, and M. Vezina.
tant administration of these two 'agents. Separating the 1987. Effects of concurrent sucralfate administration on phar-
administration of the two agents would possibly decrease the macokinetics of naproxen. Am. J. Med. 83(suppl. 313):67-73.
potential interaction of sucralfate on ketoconazole bioavail- 3. Carlson, J. A., H. J. Mann, and D. M. Canafax. 1983. Effect of
ability. On this basis, and until further studies assessing pH on disintegration and dissolution of ketoconazole tablets.
effects at different administration times are performed, rea- Am. J. Hosp. Pharm. 40(13):34-36.
sonable alternative regimens to consider are ketoconazole 4. D'Andrea, D. T., et al.'Biomed. Instrum. Technol., in press.
admini'stration at least 2 h before sucralfate or use of a 5. Espinel-Ingroff, A., and S. Shadomy. 1989. In vitro and in vivo
dosage of 2.0 g of sucralfate every 12 h, which would result evaluation of antifungal agents. Eur. J. Clin. Microbiol. Infect.
in a maximum 6-h separation of the two agents. The decision Dis. 8:352-361.
to separate the two drugs should be based on' the clinical 6. Fainsfein, V., G. P. Bodey, L. Elting, A. Naksymiuk, M.
Keating, and K. B. McCredle. 1987. Amphotericin B qr keto-
situation. conazole therapy of fungal infections in neutropenic cancer
In sunmmary, this study demonstrates that continuous patients. Arlitirnicrob. Agents Chemother. 31:11-15.
gastric pH monitoring and pH control are essential' for 7. Ferraro, J. M., and J. Q. A. Mattern II. 1984. Sucralfate
determining possible mechanisms of changes in oral keto- suspension for stomatitis. Drug Intell. Clin. P-harm. 18:153.
VOL. 35, 1991 KETOCONAZOLE BIOAVAILABILITY 1771

8. Gambertoglio, J. G., D. R. Romac, C. L. Yong, J. Birnbaum, P. gastrointestinal absorption of norfloxacin. Antimicrob. Agents
Lizak, and W. J. Amend, Jr. 1987. Lack of effect of sucralfate on Chemother. 33:99-102.
prednisone bioavailability. Am. J. Gastroenterol. 82:42-45. 19. Riley, C. M., and M. 0. James. 1986, Determination of keto-
9. Gibaldi, M., and D. Perrier. 1982. Pharmacokinetics, 2nd ed., p. conazole in the plasma, liver, lung, and adrenal of the rat by high
445-448. Marcel Dekker, Inc., New York. performance liquid chromatography. J. Chromatogr. 377:287-
10. Gold, J. W. 1984. Opportunistic fungal infections in patients 294.
with neoplastic disease. Am. J. Med. 76:458-463. 20. Shenep, J. L., D. K. Kalwinski, P. R. Hutson, S. L. George,
11. Hall, T. G., P. G. Cuddy, C. J. Glass, and M. Srikumaran. 1986. R. K. Dodge, K. P. Blankenship, and D. Thornton. 1988.
Effect of sucralfate on phenytoin bioavailability. Drug Intell. Efficacy of oral sucralfate suspension in prevention and treat-
Clin. Pharm. 20:607-611. ment of chemotherapy-induced mucositis. J. Pediatr. 113:758-
12. Hart, P. D., E. Russell, Jr., and J. S. Remington. 1969. The 763.
compromised host and infection II: deep fungal infection. J. 21. Soloman, M. A. 1986. Oral sucralfate suspension for mucositis.
Infect. Dis. 120:169-191. N. Engl. J. Med. 315:459-460.
13. Luciarelli, C. D. 1984. Chemotherapy induced oral mucositis: 22. Statistical Consultants, Inc. 1986. PCNONLIN and NONLIN84:
causes and treatment. Cancer Chemother. Update 2:1-4. software for the statistical analysis on nonlinear models. Am.
14. McEvoy, G. K. (ed.). 1990. American Hospital Formulary Stat. 40:52-57.
Service drug information '90. American Society of Hospital 23. Stavney, L. S., T. Hamilton, W. Sircus, and A. N. Smith. 1966.
Pharmacists, Bethesda, Md. Evaluation of the pH sensitive telemetering capsule in the
15. McGraw, B. F., E. J. Hesterlee, F. L. Lanza, and M. A. Tesler. estimation of gastric secretory capacity. Am. J. Dig. Dis.
1981. In vitro and in vivo evaluations of a tableted antacid and 11(10):753-760.
sucralfate, a new antiulcer agent. Am. J. Gastroenterol. 76:412- 24. Steinberg, W. H., F. A. Mina, P. G. Pick, and G. H. Frey. 1965.
415. Heidelberg capsule 1. In vitro evaluation of a new instrument
16. Miller, L. G., J. G. Prichard, C. A. White, B. Vytala, S. for measuring intragastric pH. J. Pharm. Sci. 54:772-776.
Feldman, and R. C. Bowman. 1990. Effect of concurrent sucral- 25. Van Der Meer, J. W. M., J. J. Keuning, H. W. Scheijgrond, J.
fate administration on the absorption of erythromycin. J. Clin. Heykrants, J. Van Custam, and J. Brugmans. 1980. The influ-
Pharmacol. 30:39-44. ence of gastric acidity on the bioavailability of ketoconazole. J.
17. Nagashima, R. 1981. Development and characteristics of sucral- Antimicrob. Chemother. 6:552-554.
fate. J. Clin. Gastroenterol. 3(suppl. 2):103-110. 26. Yarbrough, D. R., J. C. McAlhany, N. Cooper, and M. G.
18. Parpia, S. H., D. E. Nix, L. B. Hejmanowski, H. R. Goldstein, Weidner. 1969. Evaluation of the Heidelberg pH capsule
J. H. Wilton, and J. J. Schentag. 1989. Sucralfate reduces the method of tubeless gastric analysis. Am. J. Surg. 117:185-192.

Das könnte Ihnen auch gefallen